Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

Rodolfo Pedro Rothlin, Héctor Miguel Vetulli, Mariano Duarte, Facundo Germán Pelorosso, Rodolfo Pedro Rothlin, Héctor Miguel Vetulli, Mariano Duarte, Facundo Germán Pelorosso

Abstract

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002-2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1-7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients (NCT04355936).

Keywords: ACE2; ARDS; COVID-19; SARS-CoV-2; angiotensin II; clinical trial; telmisartan.

Conflict of interest statement

The authors declare no potential conflict of interest.

© 2020 Wiley Periodicals, Inc.

References

    1. Cardoso, V. G. , Gonçalves, G. L. , Costa‐Pessoa, J. M. , Thieme, K. , Lins, B. B. , Casare, F. A. M. , … Oliveira‐Souza, M. (2018). Angiotensin II‐induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC‐δ/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity. BMC Nephrology, 19(1), 179. 10.1186/s12882-018-0968-4
    1. Chen, Y. , Liu, Q. , & Guo, D. (2020). Emerging coronaviruses: Genome structure, replication, and pathogenesis. Journal of Medical Virology, 92, 418–423. 10.1002/jmv.25681
    1. Gurwitz, D. (2020). Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics. Drug Development Research. 2020, 1–4. 10.1002/ddr.21656
    1. Imayama, I. , Ichiki, T. , Inanaga, K. , Ohtsubo, H. , Fukuyama, K. , Ono, H. , … Sunagawa, K. (2006). Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator‐activated receptor γ. Cardiovascular Research, 72(1), 184–190. 10.1016/j.cardiores.2006.07.014
    1. Kakuta, H. , Sudoh, K. , Sasamata, M. , & Yamagishi, S. (2005). Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: Comparison with other angiotensin II type 1 receptor blockers. International Journal of Clinical Pharmacology Research, 25(1), 41–46.
    1. Li, Q. , Guan, X. , Wu, P. , Wang, X. , Zhou, L. , Tong, Y. , … Feng, Z. (2020). Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New England Journal of Medicine, 382(13), 1199–1207. 10.1056/NEJMoa2001316
    1. Liu, Y. , Yang, Y. , Zhang, C. , Huang, F. , Wang, F. , Yuan, J. , … Liu, L. (2020). Clinical and biochemical indexes from 2019‐nCoV infected patients linked to viral loads and lung injury. Science China Life Sciences, 63(3), 364–374. 10.1007/s11427-020-1643-8
    1. Lu, C.‐C. , Chen, M.‐Y. , & Chang, Y.‐L. (2020a). Potential therapeutic agents against COVID‐19: What we know so far. Journal of the Chinese Medical Association: JCMA, 1. 10.1097/JCMA.0000000000000318
    1. Lu, R. , Zhao, X. , Li, J. , Niu, P. , Yang, B. , Wu, H. , … Tan, W. (2020b). Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. The Lancet, 395(10224), 565–574. 10.1016/S0140-6736(20)30251-8
    1. Michel, M. C. , Foster, C. , Brunner, H. R. , & Liu, L. (2013). A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacological Reviews, 65, 809–848. 10.1124/pr.112.007278
    1. Paz Ocaranza, M. , Riquelme, J. A. , García, L. , Jalil, J. E. , Chiong, M. , Santos, R. A. S. , & Lavandero, S. (2020). Counter‐regulatory renin–angiotensin system in cardiovascular disease. Nature Reviews Cardiology, 17, 116–129. 10.1038/s41569-019-0244-8
    1. Schumacher, H. , & Mancia, G. (2008). The safety profile of telmisartan as monotherapy or combined with hydrochlorothiazide: A retrospective analysis of 50 studies. Blood Pressure, 17(Suppl. 1), 32–40. 10.1080/08038020802144383
    1. Sharpe, M. , Jarvis, B. , & Goa, K. L. (2001). Telmisartan: A review of its use in hypertension. Drugs, 61, 1501–1529. 10.2165/00003495-200161100-00009
    1. Stangier, J. , Su, C. A. P. F. , & Roth, W. (2000). Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. Journal of International Medical Research, 28(4), 149–167. 10.1177/147323000002800401
    1. Tikellis, C. , Bernardi, S. , & Burns, W. C. (2011). Angiotensin‐converting enzyme 2 is a key modulator of the renin‐angiotensin system in cardiovascular and renal disease. Current Opinion in Nephrology and Hypertension, 20(1), 62–68. 10.1097/MNH.0b013e328341164a
    1. Vaduganathan, M. , Vardeny, O. , Michel, T. , McMurray, J. J. V. , Pfeffer, M. A. , & Solomon, S. D. (2020). Renin‐angiotensin‐aldosterone system inhibitors in patients with Covid‐19. The New England Journal of Medicine. 382(17), 1653–1659. 10.1056/NEJMsr2005760
    1. Wan, Y. , Shang, J. , Graham, R. , Baric, R. S. , & Li, F. (2020). Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade‐long structural studies of SARS coronavirus. Journal of Virology, 94(7). e00127–20. 10.1128/jvi.00127-20
    1. Ware, L. B. , & Matthay, M. A. (2000, May 4). The acute respiratory distress syndrome. New England Journal of Medicine, 342, 1334–1349. 10.1056/NEJM200005043421806
    1. Zhang, P. , Zhu, L. , Cai, J. , Lei, F. , Qin, J.‐J. , Xie, J. , … Li, H. (2020). Association of Inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID‐19. Circulation Research, CIRCRESAHA.120.317134. 10.1161/CIRCRESAHA.120.317134

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe